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|Title:||Inhibition of Siah ubiquitin ligase function|
|Citation:||Oncogene, 2009; 28(2):289-296|
|Publisher:||Nature Publishing Group|
|A. Möller, C.M. House, C.S.F. Wong, D.B. Scanlon, M.C.P. Liu, Z. Ronai and D.D.L. Bowtell|
|Abstract:||Tumor hypoxia induces the upregulation of hypoxiainducible factor 1a (Hif-1a), which in turn induces the expression of genes including VEGF to recruit new blood vessel outgrowth, enabling tumor growth andmetasta sis. Interference with the Hif-1 pathway and neoangiogenesis is an attractive antitumor target. The hydroxylation of Hif-1a by prolyl-hydroxylase (PHD) proteins during normoxia serves as a recognition motif for its proteasomal degradation. However, under hypoxic conditions, hydroxylation is inhibitedan dfurt hermore, PHD proteins are themselves polyubiquitylated and degraded by Siah ubiquitin ligases. Our data demonstrate for the first time that inhibition of the interaction between Siah and PHD proteins using a fragment derived from a Drosophila protein (phyllopod) interferes with the PHD degradation. Furthermore, cells stably expressing the phyllopod fragment display reduced upregulation of Hif-1a protein levels and Hif-1-mediated gene expression under hypoxia. In a syngeneic mouse model of breast cancer, the phyllopod fragment reduced tumor growth and neoangiogenesis and prolonged survival of the mice. In addition, levels of Hif-1a andits target Glut-1 are reduced in tumors expressing the phyllopodfragment . These data show, in a proof-of principle study, that Siah protein, the most upstream component of the hypoxia pathway yet identified, is a viable drug target for antitumor therapies.|
|Keywords:||Ubiquitin; degradation; hypoxia|
|Rights:||© 2009 Macmillan Publishers Limited All rights reserved|
|Appears in Collections:||Medical Sciences publications|
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